Method for producing nanoparticles suspensions

ABSTRACT

The invention relates to a method for producing a suspension of an undecomposed meltable material having an average particle diameter of between 5 to 500 nm. The inventive method enables stable suspensions to be produced and is characterised in that it only requires a simple technical infrastructure in many production plants, it delivers high space-time yields, and can easily be scaled up.

[0001] This invention relates to a process for the production of a suspension of a substance which can be melted without decomposing with a mean particle diameter in the range from 5 to 500 nm.

[0002] Many potential uses in various fields have fairly recently been found for suspensions of substances with a particularly small particle size, more particularly with a particle size below 1 micrometer. Various processes are known from the literature for the production of fine-particle suspensions. Where the substances are fusible, processes in which a melt of the substances is emulsified and then cooled have proved successful.

[0003] Thus, EP-B1 0 506 197 describes a process for the production of aqueous dispersions of lipid nanoparticles in which the lipid is first melted in an aqueous phase, optionally in the presence of emulsifiers. The mixture of molten lipid and aqueous phase is then dispersed by intensive mixing, the lipid being converted in the process into nanoparticlulate droplets with a size in the range from 50 to 1,000 nm which are solidified by cooling to form the dispersion according to the invention. This process requires very intensive mixing to obtain the droplets in the nanometer range. According to the Examples, mixing with a Turrax homogenizer is not enough and a stable suspension with a particle size in the nanometer range can only be obtained by the additional use of a high-pressure homogenizer of the microfluidizer type.

[0004] The processes known from the prior art for the production of nanoparticle suspensions of fusible substances do not simultaneously satisfy the need for

[0005] a) simple and inexpensive workability, even on an industrial scale, by which is meant in particular a process involving little outlay on equipment which comprises only a few steps and still gives a high volume/time yield,

[0006] b) high storage stability of the suspensions produced and

[0007] c) the possibility of producing even concentrated suspensions.

[0008] The problem addressed by the present invention was to remedy the deficiencies of the prior art and to provide a production process which would satisfy the requirements mentioned above.

[0009] The problem stated above has been solved by the provision of a process for the production of a suspension of a substance which can be melted without decomposing with a mean particle diameter in the range from 5 to 500 nm, characterized in that

[0010] (a) an emulsion is prepared from the substance which can be melted without decomposing, a liquid phase in which the substance is poorly soluble and an effective quantity of at least one surface modifier and

[0011] (b) the resulting emulsion is expanded into a zone of reduced pressure so that the emulsion is cooled to below the melting point of the substance.

[0012] In a preferred embodiment of the invention, the mean particle diameter of the substance which can be melted without decomposing in the suspension is in the range from 10 to 300 nm and more particularly in the range from 20 to 100 nm.

[0013] The particle diameters mentioned are meant to be interpreted as the diameter in the direction of the largest linear dimension of the particles. In the production of the fine particles, particles with a size which follows a distribution curve are always obtained. The particle size may be experimentally determined, for example, by the dynamic light scattering method known to the expert.

[0014] Substances which can be melted without decomposing are understood to be substances which have a melting point or melting range of 25° to 300° C., preferably 30° to 150° C. and more particularly 35° C. to 100° C. Suitable substances are both individual chemicals and mixtures.

[0015] According to the invention, preferred substances are organic substances and, more particularly, organic substances poorly soluble in water.

[0016] The substances suitable for use in accordance with the invention are, for example, substances which are industrially used in the cosmetic and pharmaceutical preparations, in foods, in detergents/cleaners, in adhesives, in surface treatment, in hygiene products and in agriculture. Preferred substances are the substances used in cosmetic preparations such as, for example, UV protection factors, dyes, perfumes, emulsifiers, waxes, lipid layer enhancers, antioxidants, deodorants and antiperspirants. Other preferred substances are pharmacologically active substances which are used as active principles in cosmetic, dermatological and pharmaceutical preparations.

[0017] According to the invention, the liquid phase may be selected, for example, from

[0018] water,

[0019] lower aliphatic alcohols, for example those containing 1 to 4 carbon atoms, such as methanol, ethanol, isopropyl alcohol and the isomeric butanols,

[0020] polyols preferably containing 2 to 15 carbon atoms and at least two hydroxyl groups such as, for example, ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, hexylene glycol, polyethylene glycols with an average molecular weight of 100 to 1,000 dalton, glycerol, technical oligoglycerol mixtures with a degree of self-condensation of 1.5 to 10 such as, for example, technical diglycerol mixtures with a diglycerol content of 40 to 50% by weight,

[0021] lower alkyl glucosides, more particularly those containing 1 to 8 carbon atoms in the alkyl group such as, for example, methyl and butyl glucoside

[0022] and mixtures of the above-mentioned substances. Water is the preferred liquid phase.

[0023] By poor solubility is meant that at most 1% by weight, preferably at most 0.1% by weight and more particularly at most 0.01% by weight of the substance which can be melted without decomposing dissolves in the liquid phase at 20° C., based on the total weight of the solution.

[0024] Basically, the ratio by weight between the substance which can be melted without decomposing and the liquid phase is not critical and is largely determined by the need for the substance to be sufficiently well distributed in the liquid phase.

[0025] Surface modifiers in the context of the invention are substances which physically adhere to, but preferably do not chemically react with, the surface of the nanoparticles. The individual molecules of the surface modifiers adsorbed onto the surface are substantially free from intermolecular bonds. By surface modifiers are meant above all dispersants. Dispersants are also known to the expert by such terms as, for example, emulsifiers, protective colloids, wetting agents and detergents.

[0026] Suitable surface modifiers are, for example, emulsifiers of the nonionic surfactant type from at least one of the following groups:

[0027] (1) adducts of 2 to 30 mol ethylene oxide and/or 0 to 5 mol propylene oxide with linear fatty alcohols containing 8 to 22 carbon atoms, with fatty acids containing 12 to 22 carbon atoms and with alkylphenols containing 8 to 15 carbon atoms in the alkyl group;

[0028] (2) C_(12/18) fatty acid monoesters and diesters of addition products of 1 to 30 mol ethylene oxide onto glycerol;

[0029] (3) glycerol monoesters and diesters and sorbitan monoesters and diesters of saturated and unsaturated fatty acids containing 6 to 22 carbon atoms and ethylene oxide addition products thereof;

[0030] (4) alkyl mono- and oligoglycosides containing 8 to 22 carbon atoms in the alkyl group and ethoxylated analogs thereof;

[0031] (5) addition products of 2 to 60 mol ethylene oxide onto castor oil and/or hydrogenated castor oil;

[0032] (6) polyol esters and, in particular, polyglycerol esters such as, for example, polyglycerol polyricinoleate, polyglycerol poly-12-hydroxystearate or polyglycerol dimerate. Mixtures of compounds from several of these classes are also suitable;

[0033] (7) partial esters based on linear, branched, unsaturated or saturated C_(6/22) fatty acids, ricinoleic acid and 12-hydroxystearic acid and glycerol, polyglycerol, pentaerythritol, dipentaerythritol, sugar alcohols (for example sorbitol), alkyl glucosides (for example methyl glucoside, butyl glucoside, lauryl glucoside) and polyglucosides (for example cellulose);

[0034] (8) mono-, di- and trialkyl phosphates and mono-, di- and/or tri-PEG-alkyl phosphates and salts thereof;

[0035] (9) wool wax alcohols;

[0036] (10) polysiloxane/polyalkyl polyether copolymers and corresponding derivatives;

[0037] (11) mixed esters of pentaerythritol, fatty acids, citric acid and fatty alcohol according to DE-PS 1165574 and/or mixed esters of fatty acids containing 6 to 22 carbon atoms, methyl glucose and polyols, preferably glycerol or polyglycerol, and

[0038] (12) polyalkylene glycols.

[0039] The addition products of ethylene oxide and/or propylene oxide onto fatty alcohols, fatty acids, alkylphenols, glycerol monoesters and diesters and sorbitan monoesters and diesters of fatty acids or onto castor oil are known commercially available products. They are homolog mixtures of which the average degree of alkoxylation corresponds to the ratio between the quantities of ethylene oxide and/or propylene oxide and substrate with which the addition reaction is carried out.

[0040] C_(8/18) alkyl mono- and oligoglycosides, their production and their use are known from the prior art. They are produced in particular by reacting glucose or oligosaccharides with primary alcohols containing 8 to 18 carbon atoms. So far as the glycoside component is concerned, both monoglycosides where a cyclic sugar unit is attached to the fatty alcohol by a glycoside bond and oligomeric glycosides with a degree of oligomerization of preferably up to about 8 are suitable. The degree of oligomerization is a statistical mean value on which a homolog distribution typical of such technical products is based.

[0041] Typical examples of anionic emulsifiers are soaps, alkylbenzenesulfonates, alkanesulfonates, olefin sulfonates, alkylether sulfonates, glycerol ether sulfonates, α-methyl ester sulfonates, sulfofatty acids, alkyl sulfates, alkylether sulfates such as, for example, fatty alcohol ether sulfates, glycerol ether sulfates, hydroxy mixed ether sulfates, monoglyceride (ether) sulfates, fatty acid amide (ether) sulfates, mono- and dialkyl sulfosuccinates, mono- and dialkyl sulfosuccinamates, sulfotriglycerides, amide soaps, ether carboxylic acids and salts thereof, fatty acid isethionates, fatty acid sarcosinates, fatty acid taurides, N-acylamino acids such as, for example, acyl glutamates and acyl aspartates, alkyl oligoglucoside sulfates, protein fatty acid condensates (particularly wheat-based vegetable products) and alkyl (ether) phosphates. If the anionic surfactants contain polyglycol ether chains, they may have a conventional homolog distribution although they preferably have a narrow homolog distribution.

[0042] In addition, zwitterionic surfactants may be used as emulsifiers. Zwitterionic surfactants are surface-active compounds which contain at least one quaternary ammonium group and at least one carboxylate and one sulfonate group in the molecule. Particularly suitable zwitterionic surfactants are the so-called betaines, such as the N-alkyl-N, N-dimethyl ammonium. glycinates, for example cocoalkyl dimethyl ammonium glycinate, N-acylaminopropyl-N, N-dimethyl ammonium glycinates, for example cocoacylaminopropyl dimethyl ammonium glycinate, and 2-alkyl-3-carboxymethyl-3-hydroxyethyl imidazolines containing 8 to 18 carbon atoms in the alkyl or acyl group and cocoacylaminoethyl hydroxyethyl carboxymethyl glycinate. The fatty acid amide derivative known under the CTFA name of Cocoamidopropyl Betaine is particularly preferred. Ampholytic surfactants are also suitable emulsifiers. Ampholytic surfactants are surface-active compounds which, in addition to a C_(8/18) alkyl or acyl group, contain at least one free amino group and at least one —COOH— or —SO₃H— group in the molecule and which are capable of forming inner salts. Examples of suitable ampholytic surfactants are N-alkyl glycines, N-alkyl propionic acids, N-alkylaminobutyric acids, N-alkyliminodipropionic acids, N-hydroxyethyl-N-alkylamidopropyl glycines, N-alkyl taurines, N-alkyl sarcosines, 2-alkylaminopropionic acids and alkylaminoacetic acids containing around 8 to 18 carbon atoms in the alkyl group. Particularly preferred ampholytic surfactants are N-cocoalkylaminopropionate, cocoacylaminoethyl aminopropionate and C_(2/18) acyl sarcosine. Besides ampholytic emulsifiers, quaternary emulsifiers may also be used, those of the esterquat type, preferably methyl-quaternized difatty acid triethanolamine ester salts, being particularly preferred.

[0043] Protective colloids suitable as surface modifiers are, for example, natural water-soluble polymers such as, for example, gelatin, casein, gum arabic, lysalbinic acid, starch, albumin, alginic acid and alkali metal and alkaline earth metal salts thereof, water-soluble derivatives of water-insoluble natural polymers such as, for example, cellulose ethers, such as methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose or modified carboxymethyl cellulose, hydroxyethyl starch or hydroxypropyl guar, and synthetic water-soluble polymers such as, for example, polyvinyl alcohol, polyvinyl pyrrolidone, polyalkylene glycols, polyaspartic acid and poylacrylates.

[0044] According to the invention, preferred surface modifiers are nonionic or anionic surfactants and mixtures thereof. Among the nonionic surfactants, products of the addition of 2 to 60 mol ethylene oxide onto castor oil and/or hydrogenated castor oil, alkyl mono- and oligoglycosides containing 8 to 22 carbon atoms in the alkyl group and polyalkylene glycols are particularly preferred.

[0045] In the context of the invention, an effective quantity of the at least one surface modifier is the minimum quantity necessary for obtaining a stable suspension of the substance which can be melted without decomposing in the practical application of the process according to the invention. The necessary quantity can be determined by simple routine tests. The substance which can be melted without decomposing and the at least one surface modifier are generally used in a ratio by weight of 1:10 to 10:1 and preferably in a ratio by weight of 1:2 to 2:1.

[0046] In step (a) of the process according to the invention, an emulsion is prepared from the substance which can be melted without decomposing, a liquid phase in which the substance is poorly soluble and an effective quantity of at least one surface modifier. The substance which can be melted without decomposing is present in this emulsion in liquid, i.e. molten, form. Accordingly, the emulsion is prepared at a temperature above the melting point of the substance which can be melted without decomposing. A temperature 5 to 25° C. above the melting point of the substance which can be melted without decomposing is particularly preferred, a temperature 10 to 20° C. above that temperature being most particularly preferred.

[0047] If the mixture of the substance which can be melted without decomposing used in accordance with the invention and surface modifier shows a reduction in melting point, the above figures apply to the melting point of the mixture rather than the substance which can be melted without decomposing alone.

[0048] The preparation of the emulsion in step (a) of the process according to the invention can be carried out in various ways. In one variant, the substance which can be melted without decomposing is first introduced into the liquid phase and the mixture is then heated beyond the melting point of the substance to form a two-phase system. The molten substance is then emulsified by addition of one or more surface modifiers. In another variant of the process, the substance and the liquid phase are introduced together with the surface modifier(s) and then melted and emulsified together or the melt of substance and surface modifier(s) initially prepared is mixed with the liquid phase which may also contain one or more surface modifiers. In the latter case, the temperature of the liquid phase should be selected so that it is above the melting point of the mixture of substance and surface modifier(s). In yet another variant of the process, the melt of the substance may be mixed and emulsified with a solution of one or more surface modifiers in the liquid phase, the temperature of the solution having to be selected so that it is above the melting point of the substance.

[0049] In a preferred variant of step (a) of the process according to the invention, the emulsion is prepared by melting the substance which can be melted without decomposing together with the liquid phase and the at least one surface modifier.

[0050] In another preferred variant of step (a) of the process according to the invention, the emulsion is prepared by first introducing the molten substance and then adding the liquid phase and at least one surface modifier together or successively at a temperature above the melting point of the substance. In the latter case, the liquid phase may be added before or after the surface modifier.

[0051] To prepare the emulsion in step (a) of the process according to the invention, the components are mixed preferably exclusively with a stirrer of the type typically used for industrial stirred-tank reactors, for example a blade, propeller or impeller stirrer.

[0052] The emulsion prepared in step (a) of the process according to the invention is then expanded in the second step of the process into a zone of reduced pressure so that the emulsion is cooled to below the melting point of the substance. Where the mixture of the substance and the surface modifier(s) present in the emulsion has a lower melting point than the substance itself, the emulsion must be cooled to below the melting point of the mixture.

[0053] The introduction of the emulsion into the reduced pressure zone in step (b) of the process is carried out by effecting the cooling of the emulsion to below the melting point of the substance by partial evaporation of the liquid phase. The cooling process takes place in a very short time of preferably 0.01 to 5 seconds and more particularly 0.1 to 2 seconds.

[0054] The vacuum is selected so that the emulsified particles of the substance which can be melted without decomposing solidify during the expansion by evaporation cooling. Accordingly, the choice of a suitable vacuum is determined by the nature of the liquid phase and the melting point of the substance or the mixture of the substance and the surface modifier(s) and may readily be made by the expert, for example on the basis of the vapor pressure curves of the liquid phase. Where water is used as the liquid phase, a suitable vacuum is one in the range from 10 to 800 mbar. Here, cooling to ca. 60° C. is achieved, for example, at 200 mbar and cooling to ca. 20° C. at 20 mbar.

[0055] According to the invention, therefore, a pressure of 10 to 800 mbar is preferred for step (b), a pressure of 20 to 300 mbar being particularly preferred.

[0056] In one embodiment of the invention, the emulsion is expanded into the vacuum through a line equipped with a valve. Alternatively, expansion through a nozzle is also possible.

[0057] Surprisingly, the process according to the invention gives nanoparticle suspensions with mean particle diameters in the range from 5 to 500 nm without the emulsion prepared in step (a) of the process itself having to have this particle fineness.

[0058] According to the teaching of the prior art, as represented for example by EP-B 0 506 197 cited at the beginning, particles of the required size have to be produced in the emulsion initially prepared which can only be done by introducing high mechanical energy, for example through a high-pressure homogenizer. These particles then solidify on cooling without the particle size changing, more particularly becoming smaller. On the contrary, it is repeatedly pointed out in the literature that the cooling of nanoparticle emulsions of molten substances is often accompanied by agglomeration into relatively coarse particles.

[0059] By contrast, it has been found in accordance with the invention that the additional use of a high-pressure homogenizer in step (a) of the process according to the invention actually leads to a deterioration, i.e. to the formation of distinctly coarser particles.

[0060] Accordingly, in the process according to the invention, the particles of the emulsified substance are reduced in size and, at the same time, solidified to form a nanoparticle suspension by the procedure adopted in step (b). It is assumed that this is attributable to the mechanical influences occurring during expansion into the vacuum in conjunction with the sudden cooling which convert the emulsion into a suspension in fractions of a second.

[0061] The process according to the invention gives nanoparticle suspensions which show particularly high stability in storage, i.e. neither agglomerate nor sediment, even under heat stress.

[0062] The production process according to the invention is distinguished by the fact that it requires only a simple technical infrastructure available in many production plants, gives high volume/time yields, is inexpensive and can readily be scaled-up.

[0063] Another advantage of the process according to the invention is that the suspension is concentrated by the partial evaporation of the liquid phase in step (b).

[0064] Accordingly, the present invention also relates to a process as described in the foregoing in which 5 to 50% by weight and preferably 10 to 20% by weight of the liquid phase is removed from the emulsion in step (b), based on the total weight of the emulsion before expansion.

[0065] This concentration is advantageous in cases where, although a certain quantity of the liquid phase is necessary for forming the emulsion in the first step of the process, this liquid phase is problematical so far as the subsequent use of the nanoparticle suspension is concerned. Thus, where the nanoparticle suspensions are used, for example, in cosmetic or pharmaceutical preparations, it is generally desirable for various reasons, for example to avoid formulation problems or unwanted impurities, to introduce as few accompanying substances as possible—including the liquid phase of a nanoparticle suspension—into the formulation with the nanoparticles.

[0066] If desired, the nanoparticle suspensions produced in accordance with the invention can be completely freed from the liquid phase by methods known per se, preferably by evaporating the liquid phase under reduced pressure at temperatures below the melting point of the nanoparticles.

[0067] The nanoparticles are thus obtained in the form of flowable dry powders which can readily be redispersed, even after prolonged storage, and which are suitable for use, for example, in cosmetic and pharmaceutical preparations, in foods, in detergents/cleaners, in adhesives, in hygiene products and in agriculture.

[0068] The following Examples are intended to illustrate the invention.

EXAMPLES Example 1 Preparation of a Suspension of Dehyquart F 75

[0069] 6.0 kg Dehyquart F 75 (Distearoylethyl Hydroxyethylmonium Methosulfate and Cetearyl Alcohol), 6.0 kg Eumulgin B2 (polyoxyethylene-20-ceylstearyl alcohol) and 32.2 kg dist. water were introduced into a reactor and heated to 60° C. The mixture was then heated with stirring to 90-95° C. and stirred at that temperature for half an hour. The emulsion formed was expanded through a nozzle over a period of 15 minutes into a second reactor kept by evacuation at a pressure of 20 to 30 mbar. During the expansion, the dispersion was cooled from 90-95° C. to 20-25° C. 36.0 kg of a storable suspension with a mean particle size of 30 nm were obtained.

Example 2 Preparation of a Suspension of Dehyquart AU 56

[0070] 28.0 kg of suspension with a mean particle size of 60 nm were obtained as in Example 1 from 6.0 kg Dehyquart AU 56 (N-methyl triethanolammonium dialkylester methosulfate with 10% by weight isopropanol), 6.0 kg Plantacare 1200 UP (C₁₂₋₁₆ alkyl glycoside) and 19.8 kg dist. water.

Example 3 Preparation of a Suspension of Lanette O

[0071] 3.0 kg Lanette O (cetylstearyl alcohol), 3.0 kg Texapon N 70 (sodium lauryl ether sulfate+2 EO) and 15.6 kg dist. water were reacted as in Example 1, another 12.0 kg water having been introduced into the reactor into which the emulsion was expanded. 30.5 kg of suspension with a mean particle size of 200 nm were obtained.

Example 4 Preparation of a Suspension of Lanette O

[0072] 32.0 kg of suspension with a mean particle size of 200 nm were obtained as in Example 1 from 3.0 kg Lanette O, 3.0 kg Eumulgin HRE 455 (hydrogenated castor oil+40 EO in propylene glycol/water) and 33.1 kg dist. water.

Comparison Example 1 Preparation of a Suspension of Lanette O

[0073] The procedure was as described in Example 4 except that, before expansion into the second reactor, the emulsion of the starting materials was circulated three times through a high-pressure homogenizer (Cavitron). 31.5 kg of suspension with a mean particle size of more than 1,000 nm were obtained. 

1. A process for the production of a suspension of a substance which can be melted without decomposing with a mean particle diameter in the range from 5 to 500 nm, characterized in that (a) an emulsion is prepared from the substance which can be melted without decomposing, a liquid phase in which the substance is poorly soluble and an effective quantity of at least one surface modifier and (b) the resulting emulsion is expanded into a zone of reduced pressure so that the emulsion is cooled to below the melting point of the substance.
 2. A process as claimed in claim 1, characterized in that the mean particle diameter is in the range from 10 to 300 nm.
 3. A process as claimed in claim 1 or 2, characterized in that the emulsion from step (a) is prepared by melting the substance together with the liquid phase and the at least one surface modifier.
 4. A process as claimed in claim 1 or 2, characterized in that the emulsion from step (a) is prepared by initially introducing the molten substance and then adding the liquid phase and at least one surface modifier either together or successively.
 5. A process as claimed in any of claims 1 to 4, characterized in that the cooling of the emulsion to below the melting point of the substance in step (c) is effected by partial evaporation of the liquid phase.
 6. A process as claimed in any of claims 1 to 5, characterized in that the pressure in step (b) is in the range from 10 to 800 mbar and preferably in the range from 20 to 300 mbar.
 7. A process as claimed in any of claims 1 to 6, characterized in that 5 to 50% by weight and preferably 10 to 20% by weight of the liquid phase is removed from the emulsion in step (b), based on the total weight of the emulsion before expansion. 